Use of a thromboxane receptor antagonist in pregnancy-induced hypertension and related conditions

ABSTRACT

The use is described of [1R-[1 alpha (Z),2 beta ,3 beta ,5 alpha ]]-(+)-7-[5-[[(1,1&#39;-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl )cyclopentyl]-4-heptenoic acid or a physiologically acceptable salt, solvate or cyclodextrin complex thereof in the manufacture of medicaments for the therapy or prophylaxis of conditions associated with vasoconstriction and/or platelet aggregation in the uteroplacental circulation and/or excessive synthesis of thromoxane A2 in a pregnant female subject.

This invention relates to a new medical use for[1R-[1α(Z),2β,3β,5α]]-(+)-7-[5-[[(1,1'-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoicacid (hereinafter referred to as Compound A) or a physiologicallyacceptable salt, solvate or cyclodextrin complex thereof. In particular,it relates to the use of Compound A or a physiologically acceptablesalt, solvate or cyclodextrin complex thereof in the therapy orprophylaxis of conditions associated with vasoconstriction and/orplatelet aggregation in the uteroplacental circulation and/or excessivesynthesis of thromboxane A₂ in pregnant females.

Our UK Patent Specification 2097397 describes inter alia Compound Awhich is a potent thromboxane receptor blocker. We have stated thereinthat the compounds of the invention, including Compound A, inhibitthromboxane A₂ and endoperoxide mediated aggregation of blood plateletsand contraction of vascular smooth muscle and are thus of particularinterest as anti-thrombotic agents.

We have now found that Compound A or a physiologically acceptable salt,solvate or cyclodextrin complex thereof is of use in the therapy orprophylaxis of conditions associated with vasoconstriction and/orplatelet aggregation in the uteroplacental circulation and/or excessivesynthesis of thromboxane A₂ in pregnant females. Conditions which arecovered by this pathophysiology include pregnancy-induced hypertension,preeclampsia, eclampsia and intrauterine growth retardation.

Thus according to one aspect of the present invention, we provideCompound A or a physiologically acceptable salt, solvate or cyclodextrincomplex thereof for use in the manufacture of a medicament for thetherapy or prophylaxis of conditions associated with vasoconstrictionand/or platelet aggregation in the uteroplacental circulation and/orexcessive synthesis of thromboxane A₂ in a pregnant female subject.

It is preferable to employ Compound A or a physiologically acceptablesalt solvate or cyclodextrin complex thereof in the form of aformulation. The present invention therefore also provides a compositionfor use in combatting conditions associated with vasoconstriction and/orplatelet aggregation in the uteroplacental circulation and/or excessivesynthesis of thromboxane A₂ in pregnant females comprising Compound A ora physiologically acceptable salt, solvate or cyclodextrin complexthereof together, where desirable, with one or more carriers orexcipients.

In a further aspect of the invention, we provide a method of treatmentof a pregnant female subject for combatting conditions associated withvasoconstriction and/or platelet aggregation in the uteroplacentalcirculation and/or excessive synthesis of thromboxane A₂ by therapy orprophylaxis which method comprises administering to the subject aneffective amount of Compound A or a physiologically acceptable salt,solvate or cyclodextrin complex thereof.

It will, of course, be appreciated that the aforementionedpregnancy-induced hypertension preeclampsia and eclampsia are conditionswhich are not only deleterious to the female subject but which may alsolead to growth retardation of the unborn foetus and even foetal loss.Contraction of umbilical vessels by thromboxane A₂ may also lead toneonatal complications during parturition.

Compound A or a physiologically acceptable salt, solvate or cyclodextrincomplex thereof may be used according to the present invention invarious formulations for oral or parenteral administration. Suitableformulations for use according to the present invention are described inGB-B-2097397, GB-B-2127406 and UK Patent Application No. 8829793.

Suitable salts of Compound A include acid addition salts derived frominorganic and organic acids such as hydrochlorides, hyrobromides,sulphates, phosphates, maleates, tartrates, citrates, benzoates,2-chlorobenzoates, p-toluenesulphonates, methanesulphonates salicylates,fumarates, lactates, hydroxynaphthalenecarboxylates (e.g. 1-hydroxy- or3-hydroxy-2-naphthalenecarboxylates) or furoates or salts with suitablebases such as alkali metal (e.g. sodium and potassium), alkaline earthmetal (e.g. calcium or magnesium), ammonium and substituted ammonium(e.g. dimethylammonium, triethylammonium, 2-hydroxyethyldimethylammonium, piperazine, N,N-dimethylpiperazine, piperidine,ethylenediamine and choline) salts. A preferred salt of Compound A isthe hydrochloride salt. Compound A and physiologically acceptable saltsand solvates thereof are described in GB-B-2097397 and GB-B-2127406.

When Compound A is used according to the present invention in the formof a cyclodextrin complex, the complex conveniently contains a molarratio of Compound A with cyclodextrin within the range 1:1 to 1:3.

The term "cyclodextrin" means herein an unsubstituted or substituted α-,β- or γ-cyclodextrin (or a hydrate thereof) or a mixture of two or threeof them. Examples of suitable substituted cyclodextrins includesulphur-containing cyclodextrins, nitrogen-containing cyclodextrins,alkylated (e.g. methylated) cyclodextrins such as mono-, di- ortrimethylated derivatives of a cyclodextrin (e.g. of β-cyclodextrin) andhydroxyalkyl (e.g. hydroxypropyl) cyclodextrins such as hydroxypropylβ-cyclodextrin and acylated derivatives thereof. Hydroxyalkyl (e.g.hydroxypropyl) cyclodextrins such as hydroxypropyl β-cyclodextrin havebeen found to be particularly suitable.

A particularly preferred cyclodextrin complex of Compound A is theβ-cyclodextrin complex in which the molar ratio of Compound A withβ-cyclodextrin is about 1:1.

Cyclodextrin complexes of Compound A and pharmaceutical formulationscontaining them are described in our co-pending British PatentApplication No. 8829793. The cyclodextrin complexes may be prepared bymixing Compound A or the hydrochloride salt thereof with thecyclodextrin in a suitable solvent such as water or an organic solventwhich is miscible with water (e.g. an alcohol such as methanol). Thereaction may take place at any temperature in the range from 0° to 80°C. However, the mixture is preferably kept at around room temperatureand the desired complex obtained by concentrating the mixture underreduced pressure or by allowing the mixture to cool. The mixing ratio ororganic solvent with water may be suitably varied according to thesolubilities of the starting materials and products. Preferably 1 to 4moles of cyclodextrin are used for each mole of Compound A or itshydrochloride salt.

Pharmaceutical formulations containing a cyclodextrin complex ofCompound A may be prepared in conventional manner by mixing the complexwith one or more pharmaceutical carriers or excipients, for example,according to the general methods described in GB-B-2097397 andGB-B-2127406.

When Compound A or a physiologically acceptable salt, solvate orcyclodextrin complex is to he administered as an aqueous formulationfor, in particular, parenteral (e.g. intravenous) use, the compositionmay be prepared accordIng to the general methods described inGB-B-2097397 and GB-B-2127406. Alternatively, the aqueous compositionsmay be prepared by mixing Compound A or, more preferably, thehydrochloride salt thereof with cyclodextrin together with one or morepharmaceutical carriers or excipients for example as described in theExamples hereinafter. Preferably Compound A or its hydrochloride saltare dissolved in water and the remaining constituents are added thereto.

The molar ratio of Compound A or its hydrochloride salt withcyclodextrin in the aqueous composition is conveniently within the range1:1 to 1:3.

Preferably the aqueous formulation comprises the hydrochloride salt ofCompound A and β-cyclodextrin (or a hydrate thereof) at aboutphysiological pH wherein the formulation contains at least about 1.2moles of β-cyclodextrin (e.g. 1.2 to 2 moles) for every one mole of thehydrochloride salt of Compound A. Preferably the molar ratio will beabout 1:1.4 (e.g. 1:1.28).

The precise dose of Compound A or a physiologically acceptable salt,solvate or cyclodextrin complex thereof to be administered will, ofcourse, depend on a number of factors including, for example, the ageand weight of the patient and the route of administration. An effectiveoral dose, however, in the case of Compound A or a physiologicallyacceptable salt solvate or cyclodextrin complex thereof is likely to bein the range from 0.05 to 20 mg/kg body weight of patient per day,preferably in the range from 0.05 to 5 mg/kg per day.

The concentration of Compound A or the hydrochloride salt thereof in theaforementioned aqueous formulations suitable for parenteraladministration, in particular for administration by injection (e.g.Intravenously), is conveniently within the range 0.1-10 mg/ml, e.g.0.1-5 mg/ml, expressed as the free base. Preferably, the concentrationis 2 mg/ml expressed as the free base when the aqueous formulation isadministered by intravenous injection. If desired, a higherconcentration may be used and the solution may be diluted prior to usewith, for example, an isotonic saline solution or dextrose or mannitolsolution. Conveniently, solutions suitable for injection are presentedin an appropriate dose volume (e.g. 1-100 ml). Dilutions suitable forcontinuous infusion may have a concentration of Compound A or itshydrochloride salt of 0.01-0.2 mg/ml expressed as the free base. Thesolution for continuous infusion may be presented in this form, forexample in packs of 50-100 ml, or may be presented in more concentratedforms for subsequent dilution before use with, for example, an isotonicsaline solution or dextrose or mannitol solution. Alternatively smallvolumes of a more concentrated solution (e.g. 0.1-5 mg/ml) may beutilised for continuous infusion conveniently administered at a rate of0.5 to 9.9 ml/h.

The aforementioned aqueous formulations may also be adapted for oraladministration (e.g. as a capsule, syrup or solution). The preparationof suitable formulations for oral use will be within the knowledge ofpersons skilled in the art and may generally follow the proceduresdescribed in GB-B-2097397, GB-B-2127406 and in the Examples hereinafter.

The following examples are provIded in illustration of the presentinvention and should not be construed in any way as constituting alimitation thereof.

Pharmaceutical examples of parenteral injections/infusions comprisingthe hydrochloride salt of Compound A

    ______________________________________                                        (i) Hydrochloride salt of Compound A                                          equivalent to 50 mg base                                                      ______________________________________                                        β-Cyclodextrin hydrate                                                                    143 mg   166 mg    238 mg                                    Sodium hydroxide solution                                                                      to pH 7  to pH 7   to pH 7                                   Water suitable for injection                                                                   to 50 ml to 50 ml  to 50 ml                                  ______________________________________                                    

The hydrochloride salt of Compound A was dissolved in 35 ml watersuitable for injection and the β-cyclodextrin was added. This solutionwas titrated to pH 7 with 0.02 M sodium hydroxide solution and thenadjusted to volume with water suitable for injection.

The solution may then be sterilised by filtration and filled into vialsor ampoules.

    ______________________________________                                        (ii) Hydrochloride salt of Compound A                                         equivalent to 50 mg base                                                      ______________________________________                                        β-Cyclodextrin hydrate                                                                           166 mg                                                Sodium chloride         450 mg                                                pH 7.0 phosphate buffer 2.5 ml                                                Sodium hydroxide solution                                                                             to pH 7                                               Water suitable for injection                                                                          to 50 ml                                              ______________________________________                                    

The hydrochloride salt of Compound A was dissolved in approximately 25ml water suitable for injection. The β-cyclodextrin was dissolvedtherein and the resulting solution was titrated to pH 6 with 0.02 Msodium hydroxide solution and the phosphate buffer added. The sodiumchloride was added to the solution and the pH adjusted to pH 7 withsodium hydroxide. The solution was made up to volume with water suitablefor injection. A sample of this solution was filled into a glass vialwhich was sealed with a rubber plug and metal overseal. This was thenautoclaved.

    ______________________________________                                        (iii) Hydrochloride salt of Compound A                                        equivalent to 50 mg base                                                      ______________________________________                                        HydroxypropyI-β-cyclodextrin                                                                     170 mg                                                Mannitol                2.5 g                                                 pH 6.0 phosphate buffer 5.0 ml                                                Sodium hydroxide solution                                                                             to pH 6                                               Water suitable for injection                                                                          to 50 ml                                              ______________________________________                                    

The hydrochloride salt of Compound A was dissolved in approximately 25ml water suitable for injection and the hydroxypropyl-β-cyclodextrin wasadded. The mannitol was then added and the solution titrated to pH 6with 0.02 M sodium hydroxide solution. The phosphate buffer solution wasadded and the solution adjusted to volume with water suitable forinjection. The solution was then filtered and filled into glass vialswhich were sealed with rubber plugs and metal overseals. These were thenautoclaved.

    ______________________________________                                        (iv) Hydrochloride salt of Compound A                                         equivalent to 50 mg base                                                      ______________________________________                                        β-Cyclodextrin hydrate                                                                            166 mg                                               Mannitol                 2.5 g                                                Sodium acid phosphate    46 mg                                                Disodium phosphate, anhydrous                                                                          5 mg                                                 Sodium hydroxide solution                                                                              to pH 6                                              Water suitable for injection                                                                           to 50 ml                                             ______________________________________                                    

The hydrochloride salt of Compound A was dissolved in approximately 25ml water suitable for injection. The β-cyclodextrin and mannitol weredissolved therein and the solution titrated to pH 6 with 0.02 M sodiumhydroxide solution. The sodium acid phosphate and anhydrous disodiumphosphate were dissolved in water suitable for injection. This solutionwas added to the bulk solution which was made up to volume with watersuitable for injection. The solution was filtered and filled into glassampoules which were sealed and then autoclaved.

    ______________________________________                                        (v) Hydrochloride salt                                                                       Cyclodextrin                                                   of Compound A            Mixture                                              equivalent to 50 mg base                                                                     α  γ  β + γ                             ______________________________________                                        Cyclodextrin   143 mg   190 mg   119 mg                                                                              136 mg                                 Mannitol       2.5 g    2.5 g    2.5 g                                        pH 6.0 Phosphate buffer                                                                      5.0 ml   5.0 ml   5.0 ml                                       Sodium hydroxide solution                                                                    to pH 6  to pH 6  to pH 6                                      Water suitable for                                                                           to 50 ml to 50 ml to 50 ml                                     injection                                                                     ______________________________________                                    

The hydrochloride salt of Compound A was dissolved in approximately 25ml water suitable for injection and the cyclodextrin(s) was (were)added. The mannitol was then added and the solution titrated to pH 6with 0.02 M sodium hydroxide solution. The phosphate buffer solution wasadded and the solution was adjusted to volume with water suitable forinjection. The solution was then filtered and filled into glass vialswhich were sealed with rubber plugs and metal overseals.

Pharmaceutical example of an oral syrup comprising the hydrochloridesalt of Compound A

    ______________________________________                                        Hydrochloride salt of Compound A                                              equivalent to 2.5 mg base                                                     ______________________________________                                        β-cyclodextrin hydrate                                                                            9 mg                                                 Citric acid              to pH 4.5                                            Methyl hydroxybenzoate sodium                                                                          5 mg                                                 Propyl hydroxybenzoate sodium                                                                          2 mg                                                 Liquid orange flavour    qs                                                   Sucrose                  3.25 g                                               Purified water           to 5.0 ml                                            ______________________________________                                    

Dissolve the sucrose in a minimum quantity of water. Add thehydrochloride salt of Compound A and then the β-cyclodextrin withstirring; adjust the pH to 4.5 with citric acid. With continued stirringadd a solution of the hydroxybenzoate and lastly the flavour. Adjustalmost to volume with water and stir. Check the pH and adjust to 4.5with citric acid if necessary. Make up to volume with water.

I claim:
 1. A method of treatment of a pregnant female subject for combatting pregnancy-induced hypertension, preeclampsia, eclampsia or intrauterine growth retardation, either by therapy or prophylaxis, which method comprises administering to said subject an effective amount of an active ingredient, [1R-[1α(Z), 2β,3β,5α]]-(+)-7-[5-[[(1,1'-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid, or a physiologically acceptable salt, solvate or cyclodextrin complex thereof.
 2. The method as claimed in claim 1 wherein the salt is the hydrochloride salt.
 3. The method as claimed in claim 1 wherein the active ingredient is presented in a form suitable for oral or parenteral administration.
 4. The method as claimed in claim 3 wherein the active ingredient is presented in an amount sufficient to administer 0.05 to 20 mg/kg body weight per day to said pregnant female subject. 